ABSTRACT Alzheimer?s disease (AD) and cardiovascular disease (CVD) share crucial cardiometabolic and lifestyle risk factors that occur late in life, such as hypertension, hypercholesterolemia, type II diabetes, and chronic inflammation. Activation of the protease-activated receptor 2 (PAR2) has associated roles in several of the listed cardiometabolic disorders due to its position as a master regulator of chronic inflammation and pain. We recently demonstrated PAR2 has a prominent role in atherosclerosis, a pathology that frequently interconnects several CVDs, via release of vascular smooth muscle cell (VSMC)-derived proinflammatory cytokines. There is compelling evidence that PAR2 is increased in the brains of AD patients and contributes substantially to neuroinflammation. Our parent grant demonstrates PAR2 activation results in the subsequent phenotypic modulation of VSMCs in atherosclerosis. Importantly, there is substantial literature linking PAR2 to the pathogenesis of AD, although definitive behavioral studies, neuropathology, and potential mechanisms have yet to be determined. This Administrative Supplement will examine the central hypothesis that PAR2 is a novel contributor of AD progression via enhancement of neuroinflammation. Male and female VSMC-specific PAR2 mutants on a low-density lipoprotein receptor deficient (Ldlr-/-) background, as well as the utilization of a novel PAR2 pepducin inhibitor will be utilized for these studies, which are within the scope of the parent grant. We will examine this hypothesis utilizing two specific aims. Aim 1 will elucidate whether PAR2 reduction attenuates the formation and progression of atherosclerosis-induced AD with decreased amyloid beta deposition, neurofibrillary tangles, neuronal apoptosis, and neuroinflammation. Aim 2 will determine the effect of VSMC-specific PAR2 deletion on neuroinflammation and AD progression. We will utilize several core facilities to test these hypotheses, including the Behavioral Core as a part of our NIH funded Mouse Metabolic Phenotyping Center, utilizing water maze determination of cognitive function and cerebral blood flow via magnetic resonance imaging. We are highly confident that our results will yield fruitful preliminary data for the submission of a full R01 grant, which will highlight PAR2 as a potential target for the treatment of AD.